Delivery of therapeutic agents to the pulmonary system has been used for the treatment of local lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (A. J. Hickey, editor, inhalation Aerosols: Physical and Biological Basis for Therapy, New York: Marcel Dekker, Inc. 1996). Relative to systemic oral or injection drug delivery, local delivery of respiratory drugs to the lungs provides advantages because it: (1) requires smaller doses of the drug; and (2) minimizes systemic toxicity by allowing delivery directly to the site of the disease. Delivery of systemically acting agents has also been investigated, such as for the administration of proteins and peptides (e.g. insulin) as described by Patton et al., in “Inhaled insulin”, Adv. Drug. Deliv. Rev. 35, pp. 235-247 (1999). However, pulmonary delivery of drugs is limited by several major issues including poor efficiency of deposition in the respiratory tract and excessive removal of the drug by the oropharyngeal cavity, poor control over the site of deposition of the drug within the respiratory tract, poor reproducibility of dosing due to the dependence on breathing patterns of the patient, and too rapid clearance and/or absorption of the drug from the pulmonary system potentially resulting in inappropriate drug concentrations at the target site and even toxic effects.
A controlled release delivery system for drugs delivered locally to the lung would provide a very desirable method to effectively treat respiratory and systemic diseases. Moreover, controlled release of respiratory drugs may offer significant clinical benefit to millions of patients with respiratory disease by allowing them to take treatments for such diseases as asthma less frequently and to receive more prolonged and controlled relief. Controlled delivery of drugs to the lung also offers the potential for improved safety by moderating the drug peaks and troughs of immediate release drugs, which can cause added toxicity or reduced efficacy. Also, controlling the release of two or more therapeutic agents from a single particle system delivered to the pulmonary system would have significant benefits for co-localization of the agents within the respiratory tract. The likelihood of synergism or additive effects between agents would be significantly increased.
Currently available pulmonary delivery systems are not ideal, delivering inaccurate doses, requiring frequent dosing and losing significant amounts of drug in the delivery process. Most asthma drugs delivered via inhalation are immediate-release formulations that must be inhaled multiple times per day (Cochrane et al. Inhaled Corticosteroids for Asthma Therapy: Patient Compliance, Devices, and Inhalation Technique Chest, 117, pp. 542-550, 2000). This frequent inhalation tends to discourage patient compliance. When patients forget to take their medicine they may experience complications which may result in increased emergency room visits and hospitalizations. In a recent analysis of published studies of patient compliance with asthma medications, patients took the recommended doses of medication on only 20 to 73% of days (Cochrane et al. Inhaled Corticosteroids for Asthma Therapy: Patient Compliance, Devices, and Inhalation Technique, Chest. 117, pp. 542-550, 2000). The percentage of under-use days ranged from 24 to 69%. In addition, immediate release formulations often deliver drug levels that peak and trough, causing undesirable toxicity or inadequate efficacy.
Although promising, inhaled formulations face difficult challenges in maintaining effective drug concentration in the lungs for extended periods. Factors contributing to the short duration of drug action following pulmonary delivery include: (1) the rapid mucociliary clearance rates (approximately 1.7-4.9 min/min) resulting in a very short half-life for inhaled particles (approximately 0.5-2 hr) (Lansley, A. B., 1993. Mucociliary clearance and drug delivery via the respiratory tract. Adv Drug Del Rev. 11, 299-327); (2) phagocytosis of particles by the alveolar macrophages; and; (3) rapid absorption of drug molecules (Mw<1000 Da) to the systemic circulation with a mean half-time for absorption of <2 hr.
The pulmonary region has several particle clearance mechanisms. The relative importance of each clearance mechanism varies depending on the physicochemical properties of the particle. Particle retention in the pulmonary region is longer than that of the ciliated airways. After deposition, uptake of particles by alveolar macrophages is very rapid. An initial fast phase of clearance is related to phagocytosis by alveolar macrophages.
There are limited technologies available to circumvent the natural clearance mechanisms of the airways that largely prevent sustained release particles from being effective. A number of prior art references, including, but not limited to U.S. Pat. No. 6,136,295 to Edward, et al.; and U.S. Pat. No. 6,730,322 to Bernstein, et al., describe particles that have been designed to have low densities (large porous particles). Although geometrically large, those particles are aerodynamically much smaller.
Generally to achieve sustained release, particles must be delivered to the airways and avoid mucociliary clearance, uptake by alveolar macrophages, and prevention of rapid absorption from the lung. Avoiding mucociliary clearance can be achieved by avoiding particle deposition in the tracheobronchial region where ciliated epithelia are present. Generally an aerodynamic particle size must be less than around 5 μm to accomplish this. Once particles are deposited in the peripheral airways where the mucociliary clearance mechanism is not present, particles must avoid alveolar macrophage uptake that can rapidly clear therapeutic compounds. Avoidance of macrophages can be accomplished by (1) creating particles that are not recognizable as foreign particulates (stealth particles); (2) providing particles that are physically too large to be engulfed by macrophages or which delay engulfment; or (3) providing particles that are too small to be recognized by macrophages (nanoparticles).
Current sustained release pulmonary systems as described by the cited prior art generally comprise large porous particle technologies. The main problems with these systems is the low drug loading possible in the particle matrix, the special physicochemical properties of the drug required for inclusion in these particle systems, and the limits on how long drug may be sustained. The present invention overcomes these problems by using swelling particles to improve sustained release. The swelling particles of the present invention include the drug or other working agent being delivered on and/or in a biocompatible and biodegradable swellable matrix that preferably enables deep lung delivery and avoids clearance by the alveolar macrophages. In addition, the matrix materials can be modified to modulate the drug release characteristics or to improve compatibility of the drug with the matrix system.